We have made significant findings that outdoor PM2.5 (the mass concentration of particles less than 2.5 um in aerodynamic diameters) is related to all-causes and major cardiovascular disease (CVD) mortality, including ischemic heart disease (IHD), and possibly to lung cancer. However, PM2.5 in ambient air is a complex mixture that varies greatly in sources and chemical constituents. As a result, significant uncertainty remains as to the magnitude of the PM2.5 risk and which sources and/or constituents of PM2.5 pollution are most responsible for these effects. Also, it is suspected that smoking, BMI, and other factors may modify long-term air pollution-mortality risks, but these potential modifying effects and their implications for identifying potentially susceptible populations are not well understood. We propose studies to address these research needs using the NIH-AARP Diet and Health Study, a cohort of over one-half million people characterized individually for disease risk factors and followed for disease-specific mortality from 1995-96 to 2008, with over 60,000 deaths already ascertained in the first 10 years of follow-up (19,400 attributed to CVD, 11,500 to IHD, and over 7,600 to lung cancer). In addition to introducing a major new cohort in the U.S. for air pollution research, our study will carry out innovative exposure assessment, linking the detailed NIH-AARP cohort residence data to air pollution data. These data will include PM2.5 mass and gaseous co-pollutant data from the EPA's Air Quality System (AQS) network data, and PM2.5 constituent data from the EPA's nationwide Chemical Speciation Network (CSN). In another significant advance, the NIH-AARP subject mobility data will allow time-dependent exposure classification for those who move residence. With these advances, our research team propose epidemiologic analyses in the NIH-AARP cohort that will: 1) more accurately quantify associations between long-term PM2.5 air pollution and mortality; 2) identify the PM2.5 source categories and trace constituents most closely associated with total and cause-specific mortality; and, 3) identify the population subgroups at greatest risk. The U.S. EPA estimates that long-term exposure to PM2.5 in the US is associated with some 73,000 ischemic heart disease (IHD) deaths (U.S. EPA, 2010), which is on the same scale as the 85,000 IHD deaths per year caused by smoking (CDC, 2005). This study will uniquely identify air pollution source categories and PM2.5 constituents most strongly associated with all-cause, CVD and IHD mortality, a critically important advance for informing air pollution prevention policy. The study will also identify susceptible population sub-groups, and thereby provide physicians with critical clinical information for advising patients about air pollution health effects and prevention. PUBLIC HEALTH RELEVANCE: PM2.5 (the mass concentration of particles less than 2.5 um in aerodynamic diameter) in ambient air is associated with all-causes and major cardiovascular disease (CVD) mortality, including ischemic heart disease (IHD), and possibly with lung cancer. Our research team proposes epidemiologic analyses in the NIH-AARP cohort that will: 1) more accurately quantify associations between long-term PM2.5 air pollution and mortality; 2) identify the PM2.5 source categories and constituents most closely associated with mortality; and, 3) identify population subgroups at greatest PM2.5-related risk. This will enable more effective air pollution prevention policy-making, as well as provide physicians with critical clinical information for advising patients about air pollution health effects and prevention.